Purpose:
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, yet methods to predict AMD progression are decidedly lacking. While Age-Related Eye Disease Study (AREDS) categories based on the number and size of drusen can be effective in describing the current state of AMD, they are poor predictors of disease progression. In addition, the mechanism by which drusen are associated with retinal degeneration remains unclear. We hypothesize that drusen increase the transport barrier between the choroid and photoreceptors leading to photoreceptor hypoxia and subsequent retinal degeneration. To test this hypothesis we have developed a 3D computational model of retinal oxygenation that identifies hypoxic areas and predicts future retinal degeneration.

Methods:
Finite element modeling software was used to assess oxygen concentration in a generic retinal model based on morphological and physiological parameters from literature. Generic retinal morphology was then replaced by patient-specific morphology from AMD patients at AREDS stage 2 and 3 obtained using automated segmentation of optical coherence tomography images. Regions of the retina predicted to be hypoxic, and therefore at risk of future retinal degeneration, were compared to actual degeneration in the same patient at a later time point.

Results:
The results of the generic model closely recapitulated the retinal oxygen profile observed in vivo. When perturbed with drusen, this model also identified that drusen >63µm resulted in hypoxia which is the minimum size considered pathologic by AREDS. In AMD patients, longitudinal analysis of drusen topography and retinal thinning demonstrated a strong correlation between drusen height and future outer nuclear layer (ONL) thickness (R-squared=0.62). Further, identification of hypoxic regions based on early-stage morphology appears to be capable of predicting future local ONL thinning.

Conclusions:
Although more patient data is needed to validate this approach for AMD prognosis, initial results are promising. If validated, this model would represent a useful tool for clinical prognosis, demonstrate a role for hypoxia in AMD, suggest potential therapeutic interventions, and provide a surrogate endpoint for clinical trials. In addition, this approach may be useful in other retinal diseases in which hypoxia may play a similar role including retinal detachment and macular edema.